7/09/2009 @ 11:30AM

Riddle Of The Methuselah Mice

Does the same biology that leads cancer cells to run amok also cause us to age?

New research published in the journal Nature begs that question. Mice who were fed the transplant drug Rapamune late in their lives lived longer than mice in a control group. Male mice lived 9% longer, female mice 14% longer.

“This is the first compound that has been shown to slow aging when initiated in middle age,” ways Matt Kaeberlein, a researcher at the University of Washington. He predicts further increases in lifespan as the dose gets optimized in future studies.

Rapamune, sold by
Wyeth
, suppresses the immune system and raises the risk of infection, so this study isn’t a reason to start taking it. And extrapolating animal results to humans is always iffy. Experimental medicines are always thoroughly tested in animals before human tests begin, yet nine of 10 drugs that start human trials prove unsafe or ineffective. Put differently, the animal studies are wrong 90% of the time.

What’s enticing about the finding is what it may say about the biology of aging. And this research intersects with one of the hotter areas in cancer drug research. Studies of Rapamune have given birth to a whole group of cancer drugs, including the kidney cancer drugs Torisel, from Wyeth, and Afinitor, from
Novartis
, both of which are already on the market. (See “The Next Cancer Bestseller?”)
Merck
and biotech firm Ariad are working on a similar drug as a treatment for rare tumors called sarcomas.

The active ingredient in Rapamune, rapamycin, was discovered decades ago but scientists didn’t understand how the drug worked until a graduate student named David Sabatini discovered the mammalian target of rapamycin (mTOR), a protein that acts as part of a complicated set of chemical signals that causes cells to divide.

“This is a pathway that, in essence, generates mass. If you need to make things, you turn it on,” says Sabatini, now an associate professor at the MIT-affiliated Whitehead Institute. “If you don’t need to make things, like if you’re starving, you turn it off. If you’re a cancer you need to get bigger and bigger, to make more cells, you use mTOR.”

Just preventing cancer could have made the mice live longer. Mice don’t develop atherosclerosis, which means they don’t have heart attacks or strokes. Cancer is one of the most likely ways for them to die.

That’s possible, but not likely, says David Harrison, a professor at the Jackson Laboratory in Bar Harbor, Maine, who helped lead the study. “If you think of the genetic diversity and the wide variety of cancer that were found, the simplest way I can imagine to extend the lives of the mice is to retard at least some important aspects of aging,” he says.

Sabatini agrees. Experiments in simpler organisms like worms and yeast have also seemed to implicate mTOR in the aging process.

Exactly how this protein does this isn’t clear. One possibility is that mTOR is turned on by starvation–which is another way to extend life in mice. Some people have gone on calorie-restricted diets in an effort to live longer. But the benefits of calorie restriction require that mice live on a restricted diet for most of their lives. The mice in Harrison’s study lived longer after getting Rapamune when they were a year-and-a-half old, which is old age for a mouse.

Another possibility is that the drug somehow reduced the overall burden of inflammation, thereby preventing lots of diseases. A third is that as cells divide more and more often, something inside them runs down, and that slowing cell proliferation by blocking mTOR prevents aging.

More mouse experiments are in the works. Harrison says that he hopes that data from studies of humans taking mTOR drugs might also provide clues, although they may be difficult to tease out: Patients with cancer or those undergoing transplant, the people who get mTOR drugs now, don’t tend to die of old age.